8-6414878-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024596.5(MCPH1):c.228G>T(p.Val76Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,612,258 control chromosomes in the GnomAD database, including 498,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 39458 hom., cov: 29)

Exomes 𝑓: 0.79 ( 459509 hom. )

Consequence

MCPH1
NM_024596.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.21

Publications

26 publications found

Variant links:

Genes affected

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1 Gene-Disease associations (from GenCC):

microcephaly 1, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
microcephaly with intellectual disability
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MCPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 8-6414878-G-T is Benign according to our data. Variant chr8-6414878-G-T is described in ClinVar as Benign. ClinVar VariationId is 158851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5 link	c.228G>T	p.Val76Val	synonymous_variant	Exon 3 of 14	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10 link	c.228G>T	p.Val76Val	synonymous_variant	Exon 3 of 14	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes

AF:

0.702

AC:

106222

AN:

151218

Hom.:

39439

Cov.:

show subpopulations

Gnomad AFR

AF:

0.438

Gnomad AMI

AF:

0.858

Gnomad AMR

AF:

0.795

Gnomad ASJ

AF:

0.699

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.733

Gnomad FIN

AF:

0.891

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.802

Gnomad OTH

AF:

0.708

GnomAD2 exomes

AF:

0.779

AC:

194367

AN:

249410

AF XY:

0.780

show subpopulations

Gnomad AFR exome

AF:

0.428

Gnomad AMR exome

AF:

0.857

Gnomad ASJ exome

AF:

0.691

Gnomad EAS exome

AF:

0.787

Gnomad FIN exome

AF:

0.893

Gnomad NFE exome

AF:

0.799

Gnomad OTH exome

AF:

0.786

GnomAD4 exome

AF:

0.790

AC:

1154498

AN:

1460924

Hom.:

459509

Cov.:

AF XY:

0.790

AC XY:

573782

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.427

AC:

14287

AN:

33460

American (AMR)

AF:

0.851

AC:

38027

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

17965

AN:

26108

East Asian (EAS)

AF:

0.785

AC:

31120

AN:

39656

South Asian (SAS)

AF:

0.743

AC:

64020

AN:

86202

European-Finnish (FIN)

AF:

0.890

AC:

47513

AN:

53366

Middle Eastern (MID)

AF:

0.655

AC:

3771

AN:

5758

European-Non Finnish (NFE)

AF:

0.802

AC:

891728

AN:

1111304

Other (OTH)

AF:

0.763

AC:

46067

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

11137

22274

33412

44549

55686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20742

41484

62226

82968

103710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.702

AC:

106273

AN:

151334

Hom.:

39458

Cov.:

AF XY:

0.709

AC XY:

52402

AN XY:

73858

show subpopulations

African (AFR)

AF:

0.438

AC:

18010

AN:

41118

American (AMR)

AF:

0.796

AC:

12055

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

2424

AN:

3468

East Asian (EAS)

AF:

0.786

AC:

4058

AN:

5166

South Asian (SAS)

AF:

0.733

AC:

3491

AN:

4760

European-Finnish (FIN)

AF:

0.891

AC:

9324

AN:

10468

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.802

AC:

54466

AN:

67920

Other (OTH)

AF:

0.710

AC:

1479

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1369

2738

4107

5476

6845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.754

Hom.:

67224

Bravo

AF:

0.686

Asia WGS

AF:

0.747

AC:

2595

AN:

3478

EpiCase

AF:

0.784

EpiControl

AF:

0.784

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 21, 2013

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Microcephaly 1, primary, autosomal recessive

Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.44

(source)

DANN

Benign

0.56

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over